This invention relates to macrolides having activity as an antifungal agent and as an immunosuppressant.
In particular, this invention relates to analogs of the compound rapamycin, which is a compound of the following formula: ##STR2## which is useful as an antifungal agent and is useful in the suppression of the immune response.
As early as 1975, rapamycin was identified as an antifungal antibiotic harvested from a Streptomyces hygroscopicus culture, which culture was isolated from an Easter Island soil sample. See Vezina et al., J. Antibiot. 28, 721-726 (1975); and U.S. Pat. No. 3,929,992, which issued to Sehgal, et. al. Dec. 30, 1975. The ability of this compound to inhibit the immune response was first described by Martel, R. et al., Can. J. Physiol. Pharmacol., 55, 48-51 (1977). In this work, the authors show the utility of this compound in inhibiting the response to allergic encephalomyelitis, adjuvant-induced arthritis and antibody production in rats. More recently, Calne, R. Y. et al., has shown rapamycin to be immunosuppressive in rats given heterotopic heart allografts. Calne, R. Y. et al., Lancet vol. 2, p. 227 (1989). Equally important, less toxicity was said to be experienced than would be anticipated with FK-506 (U.S. Pat. No. 4,894,366, assigned to Fujisawa, which issued on Jan. 16, 1990), with which rapamycin shares some structural features.
More recently, rapamycin has been shown to be useful in combination therapy with Cyclosporin A. This combination has the advantage of reducing the amount of Cyclosporin A required to produce its immunosupressive effect, such as in heart, kidney, bowel, pancreas or other transplantation, and thereby effectively reducing the nephrotoxicity inherent in treatment with Cyclosporin A. See Stepkowski, S. M. et al., Transplantation Proceedings, vol. 23, pp 507-508 (1991).
As appreciated by those of skill in the art, and as exemplified by Harding, M. W. et al., Nature, vol. 341, p. 758-760 (1989) and Devlin, J. P. and Hargrave, K. D. Tetrahedron, vol. 45, p. 4327-4369 (1989), Cyclosporin A, FK-506, rapamycin, and analogs thereof, can be expected to share a broad range of utilities as immunosuppressive agents. Cyclosporin A, FK-506, rapamycin and analogs thereof find utility in the prevention of rejection or organ and bone marrow transplants; and in the treatment of psoriasis, and a number of autoimmune disorders such as type 1 diabetes mellitus, multiple sclerosis, autoimmune uveitis, and rheumatoid arthritis. Additional indications are discussed infra.